From Treatment to Cures for Autoimmune Diseases

Posted on by

In March 2024, CAR-T therapy was shown to be a promising though difficult and expensive option for severe SLE (NEJM 2024; 390: 687-700. Blog post: CAR T-cell Therapy: A Cure for Autoimmune Disease?)

Eric Topol has summarized more recent advances that indicate that future treatments could be safer and less costly. Instead of manipulating T-cells outside the body, an inside the body (in vivo) approach looks promising. Substack post, 12/14/25: The Exhilarating Movement From Treatment to Cures for Autoimmune Diseases

An excerpt:

“This inside the body, off-the-shelf strategy has already been shown to be safe and successful in Phase 1 trials of refractory SLE and in patients with systemic sclerosis or severe myositis…Several companies are in clinical trials with in vivo CAR T for autoimmune diseases including Capstan Therapeutics, Kite Therapeutics, Umoja Biopharma, and Shenzhen Magic-RNA. The striking progress in this field towards universal, potential one-shot cures is tempered by residual anticipated high cost, the cytokine release syndrome and neurotoxicity that can occur with CAR T. The mRNA and non-viral vectors are considered a better choice than a lentivirus vector because of the latter’s potential risk of mutagenesis and cancer…

The Soft Reset: Inverse Vaccines to Achieve Tolerance…

Tolerogenic vaccines [are] the opposite of standard vaccines that boost the immune system…Inverse vaccines are being pursued in celiac disease (Anokion, with positive clinical trial results reported earlier this year) , multiple sclerosis (ANokion, Moderna, BioNTech), and Type 1 diabetes (Diamyd Medical), rheumatoid arthritis (Janssen clinical trials.

How Progress in Cancer Fuels Autoimmune Disease Innovation

Cancer biology is the mirror image of autoimmunity. Predisposition to cancer occurs when the immune system is hypoactive, losing its protection, whereas autoimmune disease reflects hyperactivity and a dysregulated state…The B cells are a common culprit, hence the successful use of CAR T vs B cells for both diseases. The checkpoint inhibitor PD-1 (prototype Keytruda) is to cancer (cut the brakes on the immune system) as PD-1 agonists (slam on the brakes) are to autoimmune diseases. Similarly, cancer vaccines to rev up immunotherapy are the opposite of inverse, tolerogenic vaccines…

[There is a] reciprocal relationship between CAR T for cancer and autoimmunity. What’s important to emphasize is all the work to achieve in vivo, universal CAR T works for both diseases. Anything that helps cancer immunotherapy has the big dividend of also helping the efforts for curing autoimmune diseases. The new field of structural immunotherapeutics has legs to achieve precise control of our immune system vs either sets of diseases…

We’e seeing the initial stages of a renaissance vs autoimmunity. Curing instead of just treating autoimmune diseases.”

Related blog posts:

Universal Cholesterol Screening: The LEAD Initiative

Posted on by

JN Flyer et al. The Journal of Pediatrics, Volume 288, 114804. Accelerating Guideline-Recommended Universal Pediatric Lipid Screening: Launch of the LEAD Pediatric Initiative

Background: “Recent studies demonstrate only 11% of youth between 9 and 21 years of
age in the United States (US) had documented lipid screening, and 30%-60% of youth with dyslipidemia may be missed by targeted screening alone (ie, risk factors) compared with ULS [universal lipid screening]. Identification of youth living with familial hypercholesterolemia (FH) has the added benefit of triggering reverse cascade screening of family members, which can further identify at risk youth and adults.”

“In 2024, the Family Heart Foundation (FHF) established the Leveraging Evidence and Data (LEAD) for Pediatric Cholesterol Screening Initiative…The focus was not on creating new screening guidelines, but on developing strategies that will lead to better implementation of the current NHLBI/AAP screening recommendations, and with the overall goal of reducing global ASCVD [atherosclerotic cardiovascular disease] burden.”

“In FH, untreated elevated levels of LDL-C in childhood significantly increase the risk for premature atherosclerotic cardiovascular disease (ASCVD), which is the leading cause of death both in the US and worldwide. However, early initiation of statin therapy for children living with FH reduces the ASCVD risk in adulthood.”

Key points:

“Three common barriers to pediatric ULS were identified.

  • First, many parents and caregivers are not aware of the current pediatric lipid screening guidelines.
  • Second, the major rationale for ULS in young children and adolescents—early identification of a treatable genetic condition—may not be clear to patients, families, and/or clinicians.
  • Third, the values and concerns of families may be dismissed by clinicians if there is a misunderstanding of the rationale for ULS

Practical ways to improve ULS:

  • Improve education of parents and clinicians that ULS can reduce the risk of premature death from the leading cause
  • Point-of-care testing
  • EHR prompts
  • Develop physician “FH champions”

The article notes that a survey in 2017 showed that many PCPs were unaware of the national guidelines. In addition, “few were comfortable prescribing a lipid-lowering therapy.”

Recommended PCP Screening Algorithm:

My take: It is unfortunate that this article, which has an aim to improve awareness for universal pediatric lipid screening (ULS), is not an open access article. Incentives to implement lipid screening could help — screening rates are quite low despite guidelines that were published 14 yrs ago.

Related blog posts:

  • The Case for Universal Cholesterol Screening During Childhood (2024) — An excellent summary of the need/rationale for ULS. Heterozygous FH (HeFH) is the second most common potentially fatal genetic disorder in humans, affecting 1 in 250-300 people.8…Homozygous FH (HoFH) [is] much rarer, occurring in 1:250 000-1:360 000 people.. Proof that screening can make a difference:
  • Treatment Outcomes in Children and Adolescents with Hypercholesterolemia In a 20-year follow-up study, Luirink et al studied a cohort of individuals with genetically confirmed HeFH who had initiated statin therapy in childhood. When compared with their HeFH parents who had not had the benefit of childhood therapy, statins virtually eliminated excess ASCVD risk in adulthood. At age 40, 26% of parents had experienced a cardiac event and 7% had died of ASCVD, whereas only 1% of the those treated as children had needed a vascular procedure (coronary artery stenting) and none had died.

With regard to incentives, a recent commentary (DM Cutler, RS Huckman. NEJM 2025;  2025;393:2177-2180. Has Corporatization Met Its Match? The Challenge of Making Money by Keeping People Healthy) notes that the U.S. health system has financial incentives that rewards care for individuals who are sick rather than keeping patients healthy. “The system focuses its resources primarily on treatment rather than prevention…The dearth of successful business models aimed at keeping people healthy highlights one of the central challenges of the growing corporatization of health care: how to make money producing health, not just health care. The path to doing so will require fundamental changes in the incentives for individuals and institutions and, potentially, broader structural change by policymakers to increase access to or financial support for basic preventive care.”

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Long-Term Outcomes of Surgery For Excessive Drooling

Posted on by

D van den Nieuwenhof, . et al. The Journal of Pediatrics, Volume 288, 114807. Open Access! Long-Term Outcomes of Surgical Drooling Treatment in Individuals with Neurodevelopmental Disabilities: A Retrospective Cohort Study

Background: “Long-term relief of drooling remains a challenge due to the side effects of anticholinergics,13 and botulinum neurotoxin type A injections provide only a temporary relief of drooling with potential loss of effect after repeated injections.15…Surgery for drooling is often considered if moderate to severe drooling persists in children after the age of 12 years.”

Submandibular duct relocation (SMDR) “is currently considered the first choice among these surgical procedures and involves the relocation of the submandibular duct papillae to the base of the tongue, allowing saliva to flow posteriorly into the oropharynx and trigger the swallowing reflex…Since the saliva is rerouted to the oropharynx, an adequate pharyngeal swallowing phase is a prerequisite for this surgery to prevent saliva aspiration and choking. Thus, SMDR is contraindicated in patients at risk of aspiration… In these cases, SMGE [submandibular gland excision] or SDL [submandibular duct ligation] can be considered.19“

Methods: This was a retrospective cohort study with 255 patients. The authors used the visual analog scale (VAS) for drooling as the primary outcome to compare the long-term treatment outcomes of submandibular duct relocation (SMDR), submandibular gland excision (SMGE), and submandibular duct ligation (SDL) for the treatment of anterior drooling in individuals with neurodevelopmental disabilities.

Key findings:

  • A mean reduction in VAS was observed of 44.9 points for SMDR (P < .001), 27.2 for SMGE (P < .001), and 25.4 for SDL (P < .001). 
  • A significant degree of drooling recurrence was observed after SDL and SMGE at long-term follow-up

    Discussion points:

    • “SMDR is an invasive treatment requiring a night of postsurgical intubation and observation in intensive care. In specifically vulnerable children, less invasive alternatives such as SDL might therefore be preferential.”
    • “Since drooling is predominantly caused by insufficient swallowing, maintaining a balance between saliva production and clearance through swallowing is essential. SMGE and SDL inhibit saliva secretion from the submandibular glands, thereby reducing the overall volume of saliva produced.19,20 However, these procedures do not actively influence the swallowing process…A durable effect after SMGE and SDL is therefore achievable only if the reduction in saliva production reaches a threshold where the volume of saliva produced matches or falls below the individual’s capacity to swallow it effectively. On the other hand, after SMDR, the swallowing frequency itself probably increases.”
    • Selection bias: “SMDR was contraindicated for patients with inadequate swallowing… leads to a selection of less vulnerable patients with more favorable characteristics to undergo the SMDR procedure.” Thus, the improved results from SMDR over the other techniques is likely related to selection bias, though the authors adjusted the analysis “for differences in cognitive and oral motor functioning.”

    My take: Excessive drooling is a common problem in children with neurodevelopmental disabilities. This study provides useful data on surgical management.

    Video Capsule Endoscopy in VEO-IBD — Is the Juice Worth the Squeeze?

    Posted on by

    S-I Hagiwara et al.  Inflammatory Bowel Diseases, 2025; izaf144, https://doi.org/10.1093/ibd/izaf144. Open Access! Feasibility and Safety of Small Bowel Capsule Endoscopy in Very Early-Onset Inflammatory Bowel Disease: A Multi-Institutional Study

    This article shows that video capsule endoscopy (VCE) (aka small bowel capsule endoscopy [SBCE]) is feasible in children with very early-onset inflammatory bowel disease (VEO-IBD). There were 82 patients (median age, 3.8 years; median body weight, 13.0 kg) who underwent 104 SBCEs. All capsules were deployed endoscopically. Gastrointestinal patency was assessed in 95% of procedures, most commonly using patency capsules (70%).

    Key findings:

    • Observation of the entire small intestine was achieved in 100 (96.1%) patients
    • Of the remaining 4 patients, 3 could not undergo a complete observation of the entire small intestine due to battery depletion, and 1 had the capsule retained in the stomach
    • Abnormal small bowel findings were observed in 42% of patients, with aphthae being the most common (34%), followed by ulcers (18%)

    In their discussion, the authors note that due to young age, the capsules and the patency capsules required endoscopic deployment (best in duodenum). Thus, most patients received general anesthesia or intravenous sedation twice within a short period.

    The authors note that “SBCE has been reported to be superior to MRE in detecting superficial mucosal activity… [and] offers a radiation-free, relatively well-tolerated, and highly sensitive method for mucosal evaluation in VEO-IBD.”

    My take: Given the typical use of a patency capsule and thus the need for two separate anesthesia dates, I doubt the “juice is worth the squeeze” in utilizing SBCE for most patients VEO-IBD.

    Related blog posts:

    Useful repurposing of phone booth in Cotwolds, UK

    Genetic Risk Assessment and Testing for Gastrointestinal Cancers and Polyposis (2025)

    Posted on by

    K Monahan et al. Gastroenterol 2025; 169: 1147-1165. Open Access! In Our Scope of Practice: Genetic Risk Assessment and Testing for Gastrointestinal Cancers and Polyposis in Gastroenterology

    This open access review is a great up-to-date reference/resource on risks, evaluation/surveillance, and genetic testing in a wide range of disorders. This includes the myriad of polyposis syndromes as well as colorectal cancer, pancreatic cancer, and gastric cancer.

    Table 2 describes the Genetic Syndromes Associated With Risks for GI Cancers and Polyposis and the recommended surveillance/testing. For example –FAP (familial adenomatous polyposis) and JPS (juvenile polyposis syndrome):

    “Yield of MGPT in GI cancers and polyposis. MGPT has been evaluated in a number of GI cancers/polyposis. Shown in this figure are rates of positive findings on MGPT. Some of the variability among studies could be attributed to the number of genes included on the panels. [As an example,] among CRC patients, 9.9%–15% of cases were found to carry pathogenic variants in cancer-related genes.62,65,66“

    One recent new twist is the availability of direct-to-consumer testing (DTC). “Caution is advised as DTC tests can vary with regard to their quality and clinical validity. For example, some nonclinical DTC genetic tests use arrays (or “chips”) to detect single nucleotide polymorphisms associated with cancer risk in genome-wide association studies, and do not perform comprehensive sequencing of the genes of interest or evaluate for genomic deletions or duplications. DTC testing may focus on selected high-risk variants and thus incomplete test results could be falsely reassuring.

    Furthermore, DTC tests do not usually include pre- and post-test genetic counselling to inform individuals about the genomic information being evaluated, as well as the broad implications for them as an individual, and for their families.”

    My take: This article provides useful updated guidance on genetic testing for a wide range of GI disorders that predispose to cancer.

    Related blog posts:

    Is Surveillance Helpful For Patients with Barrett’s Esophagus?

    Posted on by

    Key finding: Compared with at need endoscopy, 2-yearly surveillance costs $115,563/QALY
    gained.

    Related editorial: SN Van Munster et al. Gastroenterol; 2025: 169: 1116 – 1118. Open Access! Endoscopic Surveillance for Nondysplastic Barrett’s Esophagus: Are We Violating “Primum Non Nocere”?

    “Although guidelines have historically endorsed surveillance, this endorsement has rested on observational studies vulnerable to bias and confounding. The first RCT now available provides no evidence that routine surveillance improves survival or decreases cancer burden. These findings align with an expanding body of prospective cohort evidence suggesting that the annual progression rate from NDBE to EAC [Non-Dysplastic Barrett’s Esophagus to Esophageal Adenocarcinoma] is substantially lower than historically believed—approximately 0.3%–0.5% per year,8–10,13,14 as opposed to the 2.0%–4.0% per year estimated in the early 1990s.15–17“

    The authors note that recent Dutch guidelines have been revised: “Routine surveillance is no longer recommended for low-risk Barrett’s patients—defined as those with segments with a maximal extent (Prague M) of <5 cm and no prior dysplasia.”

    My take: While Barrett’s esophagus is a rare issue for pediatric gastroenterologists, it is worth noting that these recent studies cast doubt on the benefit of routine surveillance endoscopy in patients with nondysplastic Barrett’s esophagus.

    Related blog posts:

    Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

    Christmas House Light Show Repost & More Favorite Books

    Posted on by

    I posted this link in 2019 – this nearby house continues with pretty cool lights, though they change their songs each year. There are more than 25,000 lights which are synchronized to music. Cool stuff!  Here’s a 1 minute clip: Holiday Lights 2019

    ——-

    Last year I posted a list of some of my favorite books. Here are a few of my favorite that I read from the past year (not in any particular preference order):

    • Wild Dark Shore
    • The Perfect Divorce
    • Isola
    • The Kite Runner
    • The Correspondent
    • Station Eleven

    The Risks and Absolute Risks of GLP-1 RAs and Gastrointestinal Adverse Events

    Posted on by

    C-H Chiang et al. Gastroenterol 2025; 169: 1268-1281. Glucagon-Like Peptide-1 Receptor Agonists and Gastrointestinal Adverse Events: A Systematic Review and Meta-Analysis

    With the widespread adoption of GLP-1 RAs, there have been increasing reports of adverse effects. This systematic review/meta-analysis (with 55 randomized controlled trials involving 106,395 participants) more fully describes the likelihood of GI adverse events.

    Key findings:

    • GLP-1RAs increased the risk of cholelithiasis (risk ratio [RR], 1.46; 95% CI, 1.09–1.97; 2 more cases per 1000) and probably increased the risk of GERD (RR, 2.19; 95% CI, 1.48–3.25; 4 more cases per 1000) compared with placebo
    • GLP-1RAs probably have little or no effect on the risk of other gastrointestinal or biliary events

    Figures 2 & 3 use a Forest plot to look at a large number of potential adverse gastrointestinal/biliary events. For example, cholecystitis and cholangitis had increased RR at 1.17 and 1.54 respectively. However neither reached statistical significance.

    My take: GLP-1 RAs definitely cause adverse gastrointestinal effects, especially nausea, vomiting, diarrhea, bloating and reduced appetite. More severe adverse effects are quite uncommon and are unlikely to influence the decision to use these medications.

    Related blog posts:

    Wegovy Pill Now FDA Approved

    Posted on by

    NBC News 12/22/25: FDA approves Wegovy weight loss pill from Novo Nordisk

    An excerpt:

    “The Food and Drug Administration on Monday approved a pill version of Wegovy…The Wegovy pill, as it’s called, is first oral version of a GLP-1 drug that has been brought to market for weight loss…

    In November, Novo Nordisk reached a deal with the Trump administration to sell the lowest dose of the pill for $149 a month for people who pay out of pocket, in exchange for tariff relief…

    Phase 3 clinical trial results published in the New England Journal of Medicine found that people who took the highest dose of the Wegovy pill lost 16.6% of their body weight, on average, after 64 weeks, compared with 2.2% weight loss in the placebo group…

    The company expects that the Wegovy pill will be available widely in January.”

    Related blog posts:

    Postoperative Outcomes with Tofacitinib Following Colectomy for ASUC and Real-World Outcomes for Upadacitinib in Crohn’s Disease

    Posted on by

    C Larson et al. Clin Gastroenterol Hepatol 2025; 23: 2263-2271. Postoperative Outcomes in Tofacitinib-Treated Patients With Acute Severe Ulcerative Colitis Undergoing Colectomy

    This  was a multicenter, retrospective, case-control study of patients hospitalized with ASUC who underwent colectomy, comparing patients treated with tofacitinib (n=41) prior to colectomy with infliximab-treated controls (n=68).

    Key findings:

    • Compared with tofacitinib-treated patients, infliximab-treated patients had higher overall rates of overall (44 [64.7%] vs 13 [31.7%]; P = .002) and serious (19 [27.9%] vs 3 [12%]; P = .019) postoperative complications

    My take: This study supports the safety of JAK inhibitor therapy for ASUC. It showed a significantly lower rate of overall postoperative complications in ASUC patients treated with tofacitinib compared with infliximab; the authors note that “these findings can likely be extrapolated to upadacitinib, a selective JAK inhibitor, given its similar mechanism of action.”

    J Devi et al. Clin Gastroenterol Hepatol 2025; 23: 2281-2291. Open Access! Real-World Effectiveness and Safety of Upadacitinib in Crohn’s Disease: A Multicenter Study

    Related blog posts: